Microbes are engaged in a never-ending arms race. This microbial warfare is directed in large part at conspecifics and close relatives with which they compete most intensively for access to niches and nutritional resources. One evolutionary consequence of this intense competition is the diversity of antimicrobial compounds that most species of bacteria produce. Surprisingly, there has been little attention paid to understanding either the role these compounds play in natural microbial communities or their evolution. One class of antimicrobials, the bacteriocins, has received increasing attention because of the surprisingly high levels of bacteriocin diversity observed, the widespread distribution of bacteriocins in bacteria, and the use of bacteriocins as preservatives in the food industry and as antibiotics in the human health industry. We now have a sophisticated understanding of the molecular mechanisms involved in bacteriocin-mediated killing, cell recognition and transport into the cell. However, very little effort has been focused on addressing ecological and evolutionary questions, such as: what role do these toxins play in mediating microbial interactions, what are the origins of and evolutionary relationships among this heterogeneous class of proteins, what molecular mechanisms are involved in their diversification, and what are the evolutionary responses to such an arsenal of weapons, i.e. the mechanisms of defense and the resulting evolutionary arms race? The focus of this research proposal is to specifically tackle these issues. We propose to provide a detailed description of the frequency and distribution of bacteriocin production and resistance in one clinically relevant, division of bacteria, the Enterobacteriaceae. Novel bacteriocins will then be cloned and sequenced. These data will help us to determine the phylogenetic range over which bacteriocins act, the levels of naturally occurring resistance, as well as determine the evolutionary relationships among enteric bacteriocins and their modes of diversification. In essence, what we propose is to explore the natural history of bacteriocins in search of a better understanding of how bacteriocins, and other related antimicrobials, can be used to replace, or supplement, classical antibiotics. The understanding that we gain regarding the natural role of bacteriocins, and the defenses raised against them within bacterial communities, can be directly applied to the rational application of novels antimicrobials to human health issues